http://www.nature.com/nrd/journal/vaop/ncurrent/abs/nrd4366.html
A paper by Genentech scientists John Moffat and Joachim Rudolph and the IOTA scientist David Bailey, describing the emerging relationships between target-based drug discovery (TDD) and phenotypic drug discovery (PDD) in oncology, appeared today in Nature Reviews Drug Discovery. Entitled "Phenotypic screening in cancer drug discovery – past, present and future", the paper reviews progress in oncology drug discovery over the past 15 years, and describes how defining the molecular mechanisms underlying the functional behaviour of cancer cells promises to provide new routes for cancer drug discovery through a process of "mechanism-informed phenotypic screening" (MIPS).

Their concepts are described in the figure below, taken from the paper, which illustrates how the component technologies underpinning target-based drug discovery (TDD; left panel) and phenotypic drug discovery (PDD; right panel) contribute to the respective approaches. It also indicates how dependent PDD is on the development of new technologies through which to leverage limited supplies of patient-derived tissue. By contrast, the large-scale technologies that are characteristic of TDD (such as genome sequencing, recombinant protein expression, protein NMR and X ray crystallography), and that have received massive investment from the pharmaceutical industry over the past few years, provide a steady supply of druggable molecular targets. But how relevant to clinical disease is the TDD approach? New technologies are now being developed and deployed to support PDD through patient-derived cells, high-content screening and three-dimensional cell culture. Sitting at the interface between TDD and PDD, mechanism-informed phenotypic drug discovery (MIPDD; centre) presents an opportunity to translate TDD into more clinically relevant PDD screening systems, at a time when tumour genetic profiling is uncovering the clinically relevant 'cancer signatures' that are diagnostic of underlying disease mechanisms (MMOA, molecular mechanism of action).

For more information on IOTA’s new programmes in Mechanism-informed Phenotypic Screening (MIPS) and High-content Screening (HCS), contact Dr David Bailey at IOTA Pharmaceuticals.